ABSTRACT Sjgren's syndrome (SjS) is an autoimmune disease characterized by salivary and lacrimal gland dysfunction. Although the clinical disease usually results in severe dry mouth and dry eyes, it can be systemic, affecting other organs such as the lungs, skin, kidneys, bladder, and vagina. Like most autoimmune diseases, SjS shows a sexual dimorphism with women affected >10-times more frequently than men, suggesting a strong role for sex hormones in disease susceptibility and/or progression. One common feature of SjS in both humans and animal models is mononuclear cells infiltrating salivary and lacrimal glands where they aggregate into clusters referred to as lymphocytic foci. Our recent study has identified that glandular T helper (Th)1 and Th17 cells of control and SjS patients expressed common T cell receptor (TCR)? variables (TRBV)3-1 and TRBV20, whereas TCR? variable (TRAV)8-2 was uniquely expressed by Th1 cells of SjS patients. Using SjS B6.NOD-Aec1/2 mice, we have shown that salivary Th1 cells of male mice selected for TRAV8 and TRBV16 in Th1 and Th17 cells, whereas female Th1 cells selected for TRAV8, TRAV13D-2, and TRBV23. Other studies attest our findings by identifying unique glandular TCRs in the humans and animal models of SjS. Our seminal studies clearly imply that the clonal expansion of the effector T cells with the conserved TCRs is driven by salivary gland (SG) cell antigens, and that autoimmune responses to SG cell autoantigens evidence a specific loss of immunological self-tolerance. Therefore, the primary objectives of this application are to test the specificity of the SjS TCRs with canonical SjS autoantigens and identify novel epitopes. Furthermore, using a pioneering approach, we aim to block antigen presentation of autoantigens by pathogenic T cells as a therapy to treat this debilitating disease. We hypothesize that ?glandular pathogenic T cells possess oligoclonal TCR?? repertoires that react against conserved antigenic epitopes of autoantigens and that blocking TCR activation by autoantigen-MHC complexes will prevent the development of SjS.? To test this hypothesis, we will define the diversity of the TCR?? gene repertoires for both mouse and human Th1, Th2, and Th17 cells involved in SjS using single-cell microengraving technology (Aim 1); determine the specificity of SjS TCRs with canonical SjS autoantigens and identify targets for recognition (Aim 2); and examine the therapeutic effects of blocking pathogenic TCR activation by autoantigen-MHC complexes using a rational structure-based approach (Aim 3). The significant aspect of this project is that it will provide a broader understanding of the role SG autoantigens play in modulating pathogenic T cells and their TCR repertoires. Additionally, results should establish the direction forward for generating and testing an appropriate therapy for blocking antigen presentation. Interfering with specific antigen presentation processes and pathogenic T cells will provide a novel approach by developing a personalized medical treatment for SjS patients based on specific high risk HLAs without generating general immune deficiency.